It is our longterm goal to understand the influence of apoptotic cells and their clearance mechanisms in atherogenesis. Towards this overall goal, using a differential proteomics screen, we have identified an apoptotic cell engulfment protein ligand, termed annexin-1. This protein is rapidly exported to the external leaflet of plasma membrane during apoptosis, and this protein is required for efficient engulfment of apoptotic cells by the macrophages. We also demonstrate in our recent data that crossing annexin-1 null animals with ApoE animals results in accelerated atherosclerosis. In this proposal, we will test our central premise that underlying mechanisms of apoptosis cell engulfment influence atherogenesis in collaboration with the members of the PPG. We propose to examine the functional role of annexin-1 in contributing apoptotic cell egulfment in the vessel wall, and explore the primary cell type that is affected in the annexin-1 null mice. We will test the consequences of accelerated macrophage apoptotosis together with project 2. We will investigate the mechanism of inefficient engulfment of apoptotic cells by bone-marrow-derived macrophages together with project 1, and 2. We will examine the macrophage cytokine expressing in vitro, in mouse models of atherosclerosis, and in human lesions together with projects 1, 2, and 4. The results from this investigation are anticipated to illuminate new mechanistic information on a poorly-understood process of apoptotic cell engulfment in atherosclerosis. RELEVANCE (See instructions): This study will investigate apoptotic cell engulfment process as a critical influencing factor that determine the outcome atherosclerosis. Thus, information forthcoming from this study may have a significant impact in understanding and ultimately treating human atherosclerosis.